Influence of hepatocyte nuclear factor 4a (HNF4a) gene variants on the risk of type 2 diabetes: A meta-analysis in 49,577 individuals

SILVIA SOOKOIAN; CAROLINA GEMMA; CARLOS J. PIROLA

MOLECULAR GENETICS AND METABOLISM

ACADEMIC PRESS INC ELSEVIER SCIENCE

Año: 2010 vol. 99 p. 80 - 89

1096-7192

Background: The nuclear receptor hepatocyte nuclear factor 4a (HNF4a) contributes to the regulation of a large fraction of liver and pancreatic islet transcriptomes. large fraction of liver and pancreatic islet transcriptomes. large fraction of liver and pancreatic islet transcriptomes. The nuclear receptor hepatocyte nuclear factor 4a (HNF4a) contributes to the regulation of a large fraction of liver and pancreatic islet transcriptomes. Aim: To evaluate the influence of HNF4a polymorphisms across the entire locus on the occurrence of type 2 diabetes (T2D) by means of a meta-analysis. 2 diabetes (T2D) by means of a meta-analysis. 2 diabetes (T2D) by means of a meta-analysis. To evaluate the influence of HNF4a polymorphisms across the entire locus on the occurrence of type 2 diabetes (T2D) by means of a meta-analysis. Methods: We evaluated haplotype block structure of HNF4a variants owing to linkage disequilibrium (LD). From 1455 reports, we evaluated 21 observational studies. (LD). From 1455 reports, we evaluated 21 observational studies. (LD). From 1455 reports, we evaluated 21 observational studies. We evaluated haplotype block structure of HNF4a variants owing to linkage disequilibrium (LD). From 1455 reports, we evaluated 21 observational studies. Results: Six haplotype blocks of LD were constructed with SNPs with r2 > 0.8; there were also 14 unlinked SNPs. Overall, we included 22,920 cases and 26.657 controls. Among 17 heterogeneous studies (21,881 cases and 24,915 controls), including 3 SNPs of P2 promoter region in block 1, we observed a significant association with T2D in fixed (OR 0.94, 95%CI: 0.905–0.975, p = 0.001) and random (OR 0.988, 95%CI: 0.880–0.948, p = 0.000012) model. Three homogeneous studies were evaluated in block 2 (2684 cases and 2059 controls), and a significant association with T2D was also observed: OR: 1.121, 95%CI 1.013– 1.241, p = 0.027. Three additional variants were associated with T2D: two intronic SNPs (rs4810424: OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and 2059 controls), and a significant association with T2D was also observed: OR: 1.121, 95%CI 1.013– 1.241, p = 0.027. Three additional variants were associated with T2D: two intronic SNPs (rs4810424: OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and 2059 controls), and a significant association with T2D was also observed: OR: 1.121, 95%CI 1.013– 1.241, p = 0.027. Three additional variants were associated with T2D: two intronic SNPs (rs4810424: OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). 0.880–0.948, p = 0.000012) model. Three homogeneous studies were evaluated in block 2 (2684 cases and 2059 controls), and a significant association with T2D was also observed: OR: 1.121, 95%CI 1.013– 1.241, p = 0.027. Three additional variants were associated with T2D: two intronic SNPs (rs4810424: OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and 2059 controls), and a significant association with T2D was also observed: OR: 1.121, 95%CI 1.013– 1.241, p = 0.027. Three additional variants were associated with T2D: two intronic SNPs (rs4810424: OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and 2059 controls), and a significant association with T2D was also observed: OR: 1.121, 95%CI 1.013– 1.241, p = 0.027. Three additional variants were associated with T2D: two intronic SNPs (rs4810424: OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). 0.880–0.948, p = 0.000012) model. Three homogeneous studies were evaluated in block 2 (2684 cases and 2059 controls), and a significant association with T2D was also observed: OR: 1.121, 95%CI 1.013– 1.241, p = 0.027. Three additional variants were associated with T2D: two intronic SNPs (rs4810424: OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and 2059 controls), and a significant association with T2D was also observed: OR: 1.121, 95%CI 1.013– 1.241, p = 0.027. Three additional variants were associated with T2D: two intronic SNPs (rs4810424: OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and 2059 controls), and a significant association with T2D was also observed: OR: 1.121, 95%CI 1.013– 1.241, p = 0.027. Three additional variants were associated with T2D: two intronic SNPs (rs4810424: OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). SNPs. Overall, we included 22,920 cases and 26.657 controls. Among 17 heterogeneous studies (21,881 cases and 24,915 controls), including 3 SNPs of P2 promoter region in block 1, we observed a significant association with T2D in fixed (OR 0.94, 95%CI: 0.905–0.975, p = 0.001) and random (OR 0.988, 95%CI: 0.880–0.948, p = 0.000012) model. Three homogeneous studies were evaluated in block 2 (2684 cases and 2059 controls), and a significant association with T2D was also observed: OR: 1.121, 95%CI 1.013– 1.241, p = 0.027. Three additional variants were associated with T2D: two intronic SNPs (rs4810424: OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and 2059 controls), and a significant association with T2D was also observed: OR: 1.121, 95%CI 1.013– 1.241, p = 0.027. Three additional variants were associated with T2D: two intronic SNPs (rs4810424: OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918, p < 0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595–0.995, p < 0.05, 6562 cases and 6723 controls). controls). controls). OR: 1.080, 95%CI: 1.010–1.154, p < 0.03 and rs3212183: OR: 0.843, 95%CI: 0.774–0.918,